Methylcholanthrene but not phenobarbital enhances caffeine and theophylline metabolism in cultured adult human hepatocytes.
Biotransformation of caffeine and theophylline and the effect of two well-known inducers of P-450 isozymes, namely phenobarbital (PB) and methylcholanthrene (3-MC) were studied in cultured hepatocytes from six human adult donors. Hepatocytes co-cultured with rat liver epithelial cells maintained a higher metabolic capacity than pure cultures. PB treatment of cultured hepatocytes for 3 days slightly increased the rate of caffeine metabolism 1.4 +/- 0.5-fold (N = 6) vs controls, and theophylline metabolism 1.2 +/- 0.4-fold (N = 6), whereas 3-MC treatment increased metabolism markedly 5.8 +/- 2.3- and 3.3 +/- 1.1-fold (N = 6) vs controls for caffeine and theophylline, respectively. Paraxanthine and theophylline formations from caffeine were the most induced by 3-MC. Their increase was significantly correlated (rs = 0.89, P less than 0.007) but not with TB formation, suggesting that at least two isozymes of the P-450IA family are involved in the first demethylations of caffeine. In addition, the N-1 demethylation of theophylline (mean increase of 554% vs controls) was not correlated with the N-1 demethylation of caffeine (mean to increase 247% vs controls) for the same donor after 3-MC treatment, suggesting that these two demethylations are mediated by a different P-450.
Ratanasavanh
D
D
INSERM U49, Hospital Pontchaillou, Rennes, France.
Berthou
F
F
Dreano
Y
Y
Mondine
P
P
Guillouzo
A
A
Riche
C
C
D000328:Adult; D001711:Biotransformation / Q000187:drug effects; D002110:Caffeine / Q000378:metabolism*; D002478:Cells, Cultured; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008748:Methylcholanthrene / Q000494:pharmacology*; D010634:Phenobarbital / Q000494:pharmacology*; D013806:Theophylline / Q000378:metabolism*
D002110:Caffeine; D008748:Methylcholanthrene; D013806:Theophylline; D010634:Phenobarbital